USE OF COMBINATION OF LOW-DOSE CYCLOSPORINE AND RS-61443 IN A RAT HINDLIMB MODEL OF COMPOSITE TISSUE ALLOTRANSPLANTATION

Despite technical feasibility, composite tissue allotransplantation ha s not been applied clinically because of immunosuppressive toxicity as sociated with these highly antigenic allografts. Combination immunosup pression therapy can help overcome this obstacle by allowing lower dos es of individual drugs and minimizing toxicity, RS-61443 (mycophenolat e mofetil), an effective immunosuppressant that inhibits lymphocyte pr oliferation, was tested at subtherapeutic doses in combination with cy closporine (CsA) in a rat hindlimb allotransplantation model with a ma jor antigenic mismatch at the MHC. Five groups were studied: untreated autograft controls (n=4), untreated allograft controls (n=6), allogra fts receiving low-dose CsA 1.5 mg/kg/day (n=11), allografts receiving low-dose RS-61443 15 mg/kg/day (n=17), and allografts receiving combin ation low-dose CsA 1.5 mg/kg/day + RS-61443 15 mg/kg/day (n=18), The a utograft controls survived indefinitely, while untreated allograft con trol animals developed severe rejection within 12 days. Subtherapeutic CSA and RS-61443 monotherapy groups developed acute rejection in 64% and 100% of rats, respectively, In contrast, only 11% of rats receivin g combination therapy with CSA + RS-61443 at these same subtherapeutic doses developed acute rejection (P less than or equal to 0.0013). Bon e marrow toxicity, manifested primarily by anemia and measured objecti vely by hematocrits, was reduced significantly (P=0.04) in animals rec eiving low-dose RS-61443 therapy when compared with high-dose controls . These results confirm that subtherapeutic RS-61443 + CsA combination therapy is efficacious in preventing rejection while minimizing toxic ity.